Drug resistance is one of the major obstacles for improving the prognosis of breast cancer patients. Increasing evidence has linked the association of aberrantly expressed microRNAs (miRNAs) with tumour development and progression, as well as chemoresistance. Despite recent advances, there is still little known about the potential role and mechanism of miRNAs in breast cancer chemoresistance.
Here, researchers from Shandong University found that 16 miRNAs were significantly downregulated and 11 upregulated in drug-resistant breast cancer tissues compared with drug-sensitive tissues using a miRNA microarray. Results also showed miR-489 to be one of the most downregulated miRNAs in drug-resistant tissues and cell lines as confirmed by miRNA microarray screening and real-time quantitative PCR. A decrease in miR-489 expression has been associated with chemoresistance as well as lymph node metastasis, increased tumour size, and advanced pTNM stage in breast cancer. Functional analysis revealed that miR-489 increased breast cancer chemosensitivity and inhibited cell proliferation, migration, and invasion both in vitro and in vivo. Furthermore, SPIN1, VAV3, BCL2, and AKT3 were found to be direct targets of miR-489. SPIN1 was significantly elevated in drug-resistant and metastatic breast cancer tissues, and inversely correlated with miR-489 expression. High level expression of SPIN1 was associated with higher histological grade, lymph node metastasis, advanced pTNM stage, and positive progesterone receptor (PR) status. Increased SPIN1 expression enhanced cell migration and invasion, inhibited apoptosis, and partially antagonized the effects of miR-489 in breast cancer. PIK3CA, AKT, CREB1, and BCL2 in the PI3K/Akt signalling pathway, proven to be elevated in drug-resistant breast cancer tissues, were identified as downstream effectors of SPIN1. It was further found that either inhibition of SPIN1 or overexpression of miR-489 suppressed the PI3K/Akt signalling pathway. These data indicate that miR-489 could reverse chemoresistance of breast cancer via the PI3K/Akt pathway by targeting SPIN1.

Examination of miR-489 expression in breast cancer
and its correlation
with patient survival

microrna microarray

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Chen X, Wang YW, Xing AY, Xiang S, Shi DB, Liu L, Li YX, Gao P. (2016) Suppression of SPIN1-mediated PI3K/Akt pathway by miR-489 increases chemosensitivity in breast cancer. J Pathol 239(4):459-72. [abstract]

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